CN100413860C - 作为nmda受体拮抗剂的哌啶衍生物 - Google Patents
作为nmda受体拮抗剂的哌啶衍生物 Download PDFInfo
- Publication number
- CN100413860C CN100413860C CNB028142349A CN02814234A CN100413860C CN 100413860 C CN100413860 C CN 100413860C CN B028142349 A CNB028142349 A CN B028142349A CN 02814234 A CN02814234 A CN 02814234A CN 100413860 C CN100413860 C CN 100413860C
- Authority
- CN
- China
- Prior art keywords
- piperidines
- oxo
- benzyl
- ethanamide
- title compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 title description 12
- 150000003053 piperidines Chemical class 0.000 title description 7
- 229940099433 NMDA receptor antagonist Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 378
- 238000000034 method Methods 0.000 claims abstract description 303
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 143
- 239000000203 mixture Substances 0.000 claims description 79
- 239000002253 acid Substances 0.000 claims description 58
- -1 carboxylic acyl amide Chemical class 0.000 claims description 55
- 239000002585 base Substances 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 208000002193 Pain Diseases 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 230000036407 pain Effects 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 230000000202 analgesic effect Effects 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 abstract description 16
- 108010038912 Retinoid X Receptors Proteins 0.000 abstract description 15
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 abstract description 14
- 102000014649 NMDA glutamate receptor activity proteins Human genes 0.000 abstract description 14
- 229910052720 vanadium Inorganic materials 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 10
- 239000005557 antagonist Substances 0.000 abstract description 7
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- 241000124008 Mammalia Species 0.000 abstract description 2
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- 239000000243 solution Substances 0.000 description 76
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 18
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 17
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
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- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical class CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
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- 239000007787 solid Substances 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 9
- 125000004175 fluorobenzyl group Chemical group 0.000 description 9
- 239000011347 resin Substances 0.000 description 9
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- 239000002904 solvent Substances 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 125000004043 oxo group Chemical group O=* 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 7
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- 229920002472 Starch Polymers 0.000 description 7
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 7
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- SCRPOWBFKPSGQB-UHFFFAOYSA-N 2-chloro-n-(3-oxo-4h-1,4-benzoxazin-7-yl)acetamide Chemical compound N1C(=O)COC2=CC(NC(=O)CCl)=CC=C21 SCRPOWBFKPSGQB-UHFFFAOYSA-N 0.000 description 6
- JPUYXUBUJJDJNL-UHFFFAOYSA-N 5-amino-1,3-dihydroindol-2-one Chemical compound NC1=CC=C2NC(=O)CC2=C1 JPUYXUBUJJDJNL-UHFFFAOYSA-N 0.000 description 6
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
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- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000151 deposition Methods 0.000 description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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HU0103055A HU226978B1 (en) | 2001-07-24 | 2001-07-24 | New carboxylic acid amide compounds, process for their preparation and pharmaceutical compositions containing them and their use |
HUP0103055 | 2001-07-24 | ||
HU0202213A HU225905B1 (en) | 2002-07-10 | 2002-07-10 | Solid-supported parallel synthesis of new carboxylic acid amide derivatives |
HUP0202213 | 2002-07-10 |
Publications (2)
Publication Number | Publication Date |
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CN1556805A CN1556805A (zh) | 2004-12-22 |
CN100413860C true CN100413860C (zh) | 2008-08-27 |
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CNB028142349A Expired - Lifetime CN100413860C (zh) | 2001-07-24 | 2002-07-23 | 作为nmda受体拮抗剂的哌啶衍生物 |
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CN (1) | CN100413860C (xx) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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TWI828779B (zh) * | 2018-10-17 | 2024-01-11 | 德商百靈佳殷格翰國際股份有限公司 | 4-吡-2-基甲基-嗎啉衍生物及其作為醫藥之用途 |
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DE10210779A1 (de) * | 2002-03-12 | 2003-10-09 | Merck Patent Gmbh | Cyclische Amide |
PA8575901A1 (es) * | 2002-07-18 | 2004-07-20 | Pfizer Prod Inc | Derivados de piperidina novedosos |
ES2222833B1 (es) * | 2003-07-30 | 2006-03-01 | Laboratorios Del Dr. Esteve, S.A. | Compuestos piperidinicos 1,4-disustituidos, su preparacion y su uso como medicamentos. |
MXPA06002853A (es) | 2003-09-11 | 2006-06-14 | Kemia Inc | Inhibidores citoquina. |
EP1666464A4 (en) * | 2003-09-25 | 2008-12-10 | Shionogi & Co | PIPERIDINE DERIVATIVE HAVING ANTAGONIST ACTIVITY OF THE NDMA RECEPTOR |
US20050182061A1 (en) * | 2003-10-02 | 2005-08-18 | Jeremy Green | Phthalimide compounds useful as protein kinase inhibitors |
HUP0401522A2 (en) * | 2004-07-29 | 2006-04-28 | Richter Gedeon Vegyeszet | New 4-benzylidene-piperidine derivatives, pharmaceutical compositions containing the same and process for their preparation |
HU227000B1 (en) * | 2004-07-29 | 2010-04-28 | Richter Gedeon Nyrt | Nmda receptor antagonist benzoyl urea derivatives, and pharmaceutical compositions containing them |
EP1988077A4 (en) | 2006-02-23 | 2009-09-02 | Shionogi & Co | NUCLEIC HETEROCYCLIC DERIVATIVES SUBSTITUTED BY CYCLIC GROUPS |
HUP0600810A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New sulfonamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them |
HUP0600808A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New benzamide derivatives as bradykinin antagonists, process for their preparation and pharmaceutical compositions containing them |
HUP0600809A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them |
EP1918281A1 (en) * | 2006-11-02 | 2008-05-07 | Laboratorios del Dr. Esteve S.A. | Phenylamino-substituted piperidine compounds, their preparation and use as medicaments |
JP5379692B2 (ja) | 2006-11-09 | 2013-12-25 | プロビオドルグ エージー | 潰瘍、癌及び他の疾患の治療のためのグルタミニルシクラーゼの阻害薬としての3−ヒドロキシ−1,5−ジヒドロ−ピロール−2−オン誘導体 |
EP2091948B1 (en) | 2006-11-30 | 2012-04-18 | Probiodrug AG | Novel inhibitors of glutaminyl cyclase |
JP5930573B2 (ja) | 2007-03-01 | 2016-06-15 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤の新規使用 |
ES2533484T3 (es) | 2007-04-18 | 2015-04-10 | Probiodrug Ag | Derivados de tiourea como inhibidores de la glutaminil ciclasa |
WO2009025265A1 (ja) * | 2007-08-21 | 2009-02-26 | Shionogi & Co., Ltd. | ピペラジン誘導体 |
DE102007047737A1 (de) * | 2007-10-05 | 2009-04-30 | Merck Patent Gmbh | Piperidin- und Piperazinderivate |
HUP1000312A3 (en) * | 2007-10-27 | 2011-03-28 | Richter Gedeon Nyrt | New non peptide derivatives as bradykinin bl antagonists |
CN102159076A (zh) * | 2008-07-08 | 2011-08-17 | 里克特格德翁公司 | 2-[4-(4-氟-苄基)-哌啶-1-基]-2-氧代-n-(2-氧代-2,3-二氢-苯并唑-6-基)-乙酰胺的新晶型 |
CA2734651A1 (en) * | 2008-08-21 | 2010-02-25 | Richter Gedeon Nyrt. | Methods for treating neuropathic pain |
US20100048630A1 (en) * | 2008-08-21 | 2010-02-25 | Pradeep Banerjee | Methods for treating cns disorders |
US8691866B2 (en) | 2008-12-10 | 2014-04-08 | The General Hospital Corporation | HIF inhibitors and use thereof |
HUP0900130A3 (en) | 2009-03-03 | 2012-02-28 | Richter Gedeon Nyrt | Novel crystalline hydrate, amorphous and polymorphic forms of dihydro-benzoxazole-6-yl-acetamide derivative and processes for their preparation |
NZ598685A (en) | 2009-09-11 | 2013-05-31 | Probiodrug Ag | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
KR20120107993A (ko) | 2009-12-15 | 2012-10-04 | 뉴롭, 인코포레이티드 | 신경계 장애의 치료를 위한 화합물 |
EP2536713A1 (en) | 2010-02-16 | 2012-12-26 | Pfizer Inc. | (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors |
ES2586231T3 (es) | 2010-03-03 | 2016-10-13 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
EP2545047B9 (en) | 2010-03-10 | 2015-06-10 | Probiodrug AG | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
HUP1000424A2 (en) | 2010-08-11 | 2012-05-02 | Richter Gedeon Nyrt | Use of radiprodil in attention deficit hyperactivity disorder |
ES2570167T3 (es) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Derivados de benzimidazol como inhibidores de glutaminil ciclasa |
CN107253947A (zh) * | 2011-12-27 | 2017-10-17 | 拜耳知识产权有限责任公司 | 作为杀菌剂的杂芳基哌啶和杂芳基哌嗪衍生物 |
EP2838530B1 (en) | 2012-04-20 | 2017-04-05 | UCB Biopharma SPRL | Methods for treating parkinson's disease |
WO2014127256A1 (en) * | 2013-02-18 | 2014-08-21 | The Trustees Of Columbia University In The City Of New York | Kappa opioid receptor selective compounds |
EA201790806A1 (ru) * | 2014-11-05 | 2017-11-30 | Флексус Байосайенсиз, Инк. | Иммунорегулирующие средства |
UY36390A (es) | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen |
EP3353161B1 (en) * | 2015-09-25 | 2021-07-21 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Triazole derivatives as p2y14 receptor antagonists |
ES2812698T3 (es) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
ES2897050T3 (es) | 2017-12-08 | 2022-02-28 | Boehringer Ingelheim Int | Derivados de imidazopiridina y el uso de los mismos como medicamento |
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EP3867245B1 (en) | 2018-10-17 | 2022-12-07 | Boehringer Ingelheim International GmbH | 4-pyrimidin-5-ylmethyl-morpholine derivatives and the use thereof as medicament |
EP3866854B1 (en) | 2018-10-17 | 2022-08-10 | Boehringer Ingelheim International GmbH | 4-pyridinylmethyl-morpholine derivatives and the use thereof as medicament |
CN113950478B (zh) | 2019-06-04 | 2024-02-02 | 勃林格殷格翰国际有限公司 | 作为nr2b负向调节剂的嘌呤衍生物及其作为药物的用途,特别是用于治疗抑郁病症 |
CN113234036B (zh) * | 2021-05-12 | 2023-07-14 | 斯莱普泰(上海)生物医药科技有限公司 | Nmda受体拮抗剂及其用途 |
WO2023014956A1 (en) | 2021-08-06 | 2023-02-09 | Grin Therapeutics, Inc. | Formulations of radiprodil |
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TWI828779B (zh) * | 2018-10-17 | 2024-01-11 | 德商百靈佳殷格翰國際股份有限公司 | 4-吡-2-基甲基-嗎啉衍生物及其作為醫藥之用途 |
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